Serum bilirubin and the risk of chronic obstructive pulmonary disease exacerbations

Kirstin E Brown, Don D Sin, Helen Voelker, John E Connett, Dennis E Niewoehner, Ken M Kunisaki, COPD Clinical Research Network, Kirstin E Brown, Don D Sin, Helen Voelker, John E Connett, Dennis E Niewoehner, Ken M Kunisaki, COPD Clinical Research Network

Abstract

Background: Bilirubin is a potent anti-oxidant and higher serum concentrations of bilirubin have been associated with better lung function, slower lung function decline, and lower incidence of chronic obstructive pulmonary disease (COPD). We sought to determine whether elevated bilirubin blood concentrations are associated with lower risk for acute exacerbations of COPD (AECOPD).

Methods: We performed a secondary analyses of data in the Simvastatin for Prevention of Exacerbations in Moderate-to-Severe COPD (STATCOPE) and the Azithromycin for Prevention of Exacerbations of COPD (MACRO) studies. We used time-dependent multivariable Cox proportional hazards analyses, using bilirubin concentrations prior to first AECOPD as the exposure variable and time to first AECOPD as the outcome variable. STATCOPE was used for model development, with validation in MACRO.

Results: In STATCOPE (n = 853), higher bilirubin was associated with a lower but statistically insignificant hazard for AECOPD, (adjusted hazard ratio [aHR] 0.89 per log10 increase [95%CI: 0.74 to 1.09; p = 0.26]). In the validation MACRO study (n = 1018), higher bilirubin was associated with a significantly lower hazard for AECOPD (aHR 0.80 per log10 increase [95%CI: 0.67 to 0.94; p = 0.008]).

Conclusions: Bilirubin may be a biomarker of AECOPD risk and may be a novel therapeutic target to reduce AECOPD risk.

Trial registrations: ClinicalTrials.gov NCT01061671 (registered 02 February 2010) and ClinicalTrials.gov NCT00325897 (registered 12 May 2006).

Keywords: Bilirubin; Biomarker; Chronic obstructive; Pulmonary disease.

Conflict of interest statement

Ethics approval and consent to participate

Ethics approval was obtained at each study site in the original trials from which this secondary analysis was conducted. All participants provided informed consent.

Consent for publication

N/A

Competing interests

DDS has received advisory board honoraria, research funding and speaking fees from AstraZeneca, meeting honoraria and research funding from Boehringer Ingelheim, research funding from Merck Frosst, and advisory board honoraria from Novartis.

DEN has received consulting fees from GlaxoSmithKline, Boehringer Ingelheim, and AstraZeneca.

KEB, HV, JEC, and KMK declare no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

    1. Donaldson GC, Seemungal TAR, Bhowmik A, Wedzicha JA. Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax. 2002;57:847–852. doi: 10.1136/thorax.57.10.847.
    1. Seemungal TAR, Donaldson GC, Paul EA, Bestall JC, Jeffries DJ, Wedzicha JA. Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1998;157:1418–1422. doi: 10.1164/ajrccm.157.5.9709032.
    1. Schmidt SAJ, Johansen MB, Olsen M, Xu X, Parker JM, Molfino NA, Lash TL, Sørensen HT, Christiansen CF. The impact of exacerbation frequency on mortality following acute exacerbations of COPD: a registry-based cohort study. BMJ Open. 2014;4:e006720. doi: 10.1136/bmjopen-2014-006720.
    1. Zheng JP, Kang J, Huang SG, Chen P, Yao WZ, Yang L, Bai CX, Wang CZ, Wang C, Chen BY, Shi Y, Liu CT, Chen P, Li Q, Wang ZS, Huang YJ, Luo ZY, Chen FP, Yuan JZ, Yuan BT, Qian HP, Zhi RC, Zhong NS. Effect of carbocisteine on acute exacerbation of chronic obstructive pulmonary disease (PEACE study): a randomised placebo-controlled study. Lancet. 2008;371:2013–2018. doi: 10.1016/S0140-6736(08)60869-7.
    1. Zheng JP, Wen FQ, Bai CX, Wan HY, Kang J, Chen P, Yao WZ, Ma LJ, Li X, Raiteri L, Sardina M, Gao Y, Wang BS, Zhong NS, PANTHEON study group Twice daily N-acetylcysteine 600 mg for exacerbations of chronic obstructive pulmonary disease (PANTHEON): a randomised, double-blind placebo-controlled trial. Lancet Respir Med. 2014;2:187–194. doi: 10.1016/S2213-2600(13)70286-8.
    1. Decramer M, Rutten-van Mölken M, Dekhuijzen PN, Troosters T, van Herwaarden C, Pellegrino R, van Schayck CP, Olivieri D, Del Donno M, De Backer W, Lankhorst I, Ardia A. Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (bronchitis randomized on NAC cost-utility study, BRONCUS): a randomised placebo-controlled trial. Lancet. 2005;365:1552–1560. doi: 10.1016/S0140-6736(05)66456-2.
    1. Stocker R, Glazer AN, Ames BN. Antioxidant activity of albumin-bound bilirubin. Proc Natl Acad Sci U S A. 1987;84:5918–5922. doi: 10.1073/pnas.84.16.5918.
    1. Sedlak TW, Saleh M, Higginson DS, Paul BD, Juluri KR, Snyder SH. Bilirubin and glutathione have complementary antioxidant and cytoprotective roles. Proc Natl Acad Sci U S A. 2009;106:5171–5176. doi: 10.1073/pnas.0813132106.
    1. Brandes RP, Weissmann N, Schröder K. NADPH oxidases in cardiovascular disease. Free Radic Biol Med. 2010;49:687–706. doi: 10.1016/j.freeradbiomed.2010.04.030.
    1. Curjuric I, Imboden M, Adam M, Bettschart RW, Gerbase MW, Künzli N, Rochat T, Rohrer L, Rothe TB, Schwartz J, Stolz D, Tschopp JM, von Eckardstein A, Kronenberg F, Probst-Hensch NM. Serum bilirubin is associated with lung function in a Swiss general population sample. Eur Respir J. 2014;43:1278–1288. doi: 10.1183/09031936.00055813.
    1. Apperley S, Park HY, Holmes DT, Man SFP, Tashkin D, Wise RA, Connett JE, Sin DD. Serum bilirubin and disease progression in mild COPD. Chest. 2015;148:169–175. doi: 10.1378/chest.14-2150.
    1. Horsfall LJ, Rait G, Walters K, Swallow DM, Pereira SP, Nazareth I, Petersen I. Serum bilirubin and risk of respiratory disease and death. JAMA. 2011;305:691–697. doi: 10.1001/jama.2011.124.
    1. Criner GJ, Connett JE, Aaron SD, Albert RK, Bailey WC, Casaburi R, Cooper JA, Jr, Curtis JL, Dransfield MT, Han MK, Make B, Marchetti N, Martinez FJ, Niewoehner DE, Scanlon PD, Sciurba FC, Scharf SM, Sin DD, Voelker H, Washko GR, Woodruff PG, Lazarus SC, COPD clinical research network; Canadian Institutes of Health Research Simvastatin for the prevention of exacerbations in moderate-to-severe COPD. N Engl J Med. 2014;370:2201–2210. doi: 10.1056/NEJMoa1403086.
    1. Albert RK, Connett J, Bailey WC, Casaburi R, Cooper JA, Jr, Criner GJ, Curtis JL, Dransfield MT, Han MK, Lazarus SC, Make B, Marchetti N, Martinez FJ, Madinger NE, McEvoy C, Niewoehner DE, Porsasz J, Price CS, Reilly J, Scanlon PD, Sciurba FC, Scharf SM, Washko GR, Woodruff PG, Anthonisen NR, COPD Clinical Research Network Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011;365:689–698. doi: 10.1056/NEJMoa1104623.
    1. Nicolau GY, Haus E, Lakatua DJ, Bogdan C, Sackett-Lundeen L, Popescu M, Petrescu E, Robu E, Reilly C. Circannual rhythms of laboratory parameters in serum of elderly subjects. Evaluation by cosinor analysis. Endocrinologie. 1986;24:281–292.
    1. Schwertner HA, Vitek L. Gilbert syndrome, UGT1A1*28 allele, and cardiovascular disease risk: possible protective effects and therapeutic applications of bilirubin. Atherosclerosis. 2008;198:1–11. doi: 10.1016/j.atherosclerosis.2008.01.001.
    1. Lin J, O'Donnell CJ, Schwaiger JP, Cupples LA, Lingenhel A, Hunt SC, Yang S, Kronenberg F. Association between the UGT1A1*28 allele, bilirubin levels, and coronary heart disease in the Framingham heart study. Circulation. 2006;114:1476–1481. doi: 10.1161/CIRCULATIONAHA.106.633206.
    1. Stender S, Frikke-Schmidt R, Nordestgaard BG, Grande P, Tybjaerg-Hansen A. Genetically elevated bilirubin and risk of ischaemic heart disease: three Mendelian randomization studies and a meta-analysis. J Intern Med. 2013;273:59–68. doi: 10.1111/j.1365-2796.2012.02576.x.
    1. Lo SF, Kytzia HJ, Schumann G, Swartzentruber M, Vader HL, Weber F, Doumas BT. Interlaboratory comparison of the Doumas bilirubin reference method. Clin Biochem. 2009;42:1328–1330. doi: 10.1016/j.clinbiochem.2009.05.007.
    1. O’Malley SS, Wu R, Mayne ST, Jatlow PI. Smoking cessation is followed by increases in serum bilirubin, an exogenous antioxidant associated with lower risk of lung cancer and cardiovascular disease. Nicotine Tob Res. 2014;16:1145–1149. doi: 10.1093/ntr/ntu067.
    1. Wei J, Zhao H, Fan G, Li J. Bilirubin treatment suppresses inflammation in a rat model of smoke-induced emphysema. Biochem Biophys Res Commun. 2015;465:180–187. doi: 10.1016/j.bbrc.2015.07.133.

Source: PubMed

Sponsors en medewerkers

Medische omstandigheden

Geneesmiddelinterventies

3
Abonneren